As heart failure (HF) continues to be characterized by diminished quality of life and high mortality rate, it is crucial to continue our efforts to elucidate molecular pathological mechanisms as a basis for the development of novel therapies. Myocardial injury after an ischemic insult contributes largely to the development of the chronic HF syndrome. The sponsor's (Dr. Walter J. Koch) laboratory has identified a key role for G protein- coupled receptor (GPCR) kinase-2 (GRK2) in the pathophysiology of injured and stressed myocardium. It is classically known that GRK2 phosphorylates agonist activated GPCRs, such as b-adrenergic receptors (bARs) in the heart, triggering the process of desensitization. Termination of GPCR signaling is followed by the recruitment of b-arrestins, which leads to physical uncoupling of the G protein from the receptor. Interestingly, b-arrestins, acting downstream of GRK activity, can also initiate intracellular signaling pathways through novel kinase scaffolding functions and independently of G protein signaling. The focus of the Koch laboratory over the last two decades has been studying post-receptor signaling regulated by the desensitization machinery in cardiac myocytes. More specifically, the lab has mainly focused in GRKs but it is timely to investigate the role of b-arrestins since it is clear they are novel regulators of G protein-independent signaling. Since the sympathetic nervous system appears to play a key role in stem cells egress from the bone marrow, we are interested in how adrenergic signaling regulation may affect repair of ischemic myocardium through regeneration mechanisms in addition to how b-arrestins may later the injury process after ischemia. Therefore, the goal of this proposal is to discover novel roles for b-arrestins in myocardial ischemic injury and repair. Importantly, preliminary data suggests involvement of b-arrestins in bone marrow-derived cardiac progenitor cell growth and function. Therefore, it appears significant to address the role of b-arrestins in cardiac injury and repair. PUBLIC HEALTH RELEVANCE: Considering escalating numbers of individuals experiencing diminished quality of life and high morbidity rate due to heart failure, it is of paramount importance to continue our efforts to understand the underlying pathological mechanisms of the syndrome. In this study, we propose to investigate the scaffolding and signaling proteins b-arrestin1 and b -arrestin2 and their involvement in the repair and regeneration of the injured myocardium. Additionally, we will investigate their role in cardiac stem and progenitor cell activation, with hopes to contribute to the development of novel treatments.